The present invention relates to compositions comprising β-glucans and specific immunoglobulins, and to methods of therapy using the compositions.
β-glucans are major structural components of yeast, fungi, and algae. Glucans are polymers of glucose that exist in both branched and unbranched forms. The polymers can exist as single strands with helical conformation, or as a complex of multiple strands that form a multi-stranded helix stabilized by hydrogen bonding.
β-glucans have been shown to have an effect upon various aspects of the immune response, such as humoral and cell-mediated immunity. When β-glucans are administered to experimental animals, the animals exhibit a wide range of immunomodulating and immunostimulating biological activities. These include nonspecific resistance against a variety of pathogenic challenges, promotion of wound healing, adjuvant effects when coadministered with any of bacterial, fungal, protozoal, or viral antigens, prolonged survival time in tumor-bearing animals, enhancement of bone marrow recovery and survival of lethally-irradiated mice, and reduction of serum cholesterol levels.
Administration of β-glucans, particularly (1→3)β-D-glucans, enhances host resistance to a variety of experimentally-induced bacterial (S. aureus, E. coli, K. pneunomiae, S. pyogenes, M. tuberculosis, M. pyogenes), viral (Murin viral hepatitis, Venezuelan equine encephalomyelitis virus, HIV), fungal (C. albicans, C. neoformans) and parasitic infections. β-glucans exert a significant beneficial effect on infectious episodes in animals with chemotherapy-induced immunosuppression.
All glucans, especially the soluble (1→3)β-glucans, and more particularly the branched (1→3)β-glucans, appear to be capable of inducing activation of macrophages and neutrophils, and are used as biological response mediators. Recent evidence suggests that the anti-infective efficacy of (1→3)β-glucans is attributable, at least in part, to macrophage activation induced by binding of the glucan to two specific receptors.
Studies of soluble β-glucans in animals and humans have shown them to be non-antigenic and non-virulent. While β-glucans induce toxicity, within certain ranges they can retain their activity in vivo without an unacceptable toxicity profile. β-glucans which do not induce high levels of cytokines in vivo generally exhibit lower toxicity at higher amounts, but also generally exhibit lower potency. However, the potential for particulate glucans in immunotherapy is tempered by findings that their intravenous injection is associated with undesirable side effects, including hepatosplenomegaly, granuloma formation and microembolism.
Conventional treatment of bacterial infection entails the administration of antibiotics and/or standard IGIV. Standard IGIV is a composition comprising non-specific immunoglobulin. It contains antibodies typically found in a donor population which has not been stimulated by immunization with specific antigens. Combinations of β-glucans with both antibiotics and standard IGIV have been reported. Reports of combinations of β-glucans with standard IGIV and zinc describe improved response to β-glucans as a result of a poorly-defined nonspecific stimulation of immune mechanisms by the standard IGIV and zinc, and combinations of the β-1,3-linked triple-helical glucans extracted from S. cerevisiae with conventional antibiotic therapies have demonstrated increased efficacy as compared to the β-glucan alone. No combination of β-glucan with antibodies specific to a single species of pathogenic microorganisms has been described. Indeed, where standard immunoglobulins and glucans have been combined, non-specific stimulation of immune mechanisms by the standard immunoglobulin, rather than any specific effect, has been credited with any observed differences in overall effect vis-a-vis the use of glucan alone. Soltys et al., Veterinary Immunology and Immunopathology 42:379–388 (1994).